Androstane hydrazone derivatives and methods for their manufacture



United States Patent 3,264,331 ANDROSTANE HYDRAZONE DERIVATIVES AND METHODS FOR THEIR MANUFACTURE Cecil H. Robinson, Timonium, Md., and Lawrence E.

Finckenor, Wayne, N.J., assignors to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey N0 Drawing. Filed July 23, 1964, Ser. No. 384,791

- 7 Claims. (Cl. 260397.5)

This application relates to novel steroidal derivatives, to methods for their manufacture, and to novel intermediates produced thereby. More particularly, this application relates to substituted hydrazone derivatives of steroids of the androst-ane series which are valuable as therapeutics per se or as intermediates in the preparation of other therapeutically valuable compounds. In particular, this application relates to steroids or" the androstane series having at C-3 and/ or at C-17 a hydrozone derivative substituted by and wherein W is lower alkanoyl; B is a member selected from the group consisting of hydrogen and lower alkanoyl; B is a member selected from the group consisting of hydrogen and lower alkyl; X is a member selected from the group consisting of hydrogen and fluorine; Y is a member selected from the group consisting of hydrogen and (H, 50H); and when Y is hydrogen, X is hydrogen; Z is a member selected from the group consisting of R being a member selected from the group consisting of hydrogen and an acyl radical of a hydrocarbon carboxylic acid having up to 8 carbon atoms, and A being a member selected from the group consisting of hydrogen, ethinyl, and lower alkyl; and Z is a member selected from the ice group consisting of keto, (H, 50R), and a mono-lower alkanoyl hydrazone derivative, and when Z is monolo'wer alkanoyl hydrazone, B is hydrogen.

Also included in my invention are 17-dilower alkanoylhydr-azone androstanes of the following Formula III:

E (III) II wherein T is a member selected from the group consisting of keto and (H, 50R), and R, X, Y, and W are as defined for Formulae I and II. The compounds of above Formula III are valuable as intermediates in preparing 3-keto- 17-mono-acylhydrozono-A-ring-saturated androstanes of Formula II.

The lower alkanoyl substituents on the hydrazone function at C-3 and/ or C-l7 contemplated in this invention are those having up to 7-carbon atoms, such as, formyl, acetyl, caproyl, and the like.

By lower alkyl is contemplated hydrocarbon radicals, straight chain and branched, having up to 7 carbon atoms, including radicals such as methyl, ethyl, propyl, isopropyl, t-butyl, hexyl, heptyl, and the like.

Illustrative of the hydrocarbon carboxylic acid esters contemplated at 0-3 and at 0-17 are lower alkanoates such as acetate, propionate, butyrate, valerate, caproate, and t-butyl acetate; esters from unsaturated aliphatic acids such as tetrolate and acrylate; aroyl esters such as benzoate and toluate; and esters from dibasic organic acids such as succinate, phthalate, and sulfobenzoate. Also included in the term acid radical are the alkali metal salts of the dibasic car-boxylic acid esters.

The above definition of the novel compounds of this invention should not be strictly construed but rather should be considered to admit as equivalent compounds those having the presence of other substituents on the steroid nucleus particularly at positions 2, 6, 9, 11, and 16 such as 2ot-methyl, Got-methyl, 6a-fluoro, 6OL-ChlOIO, 904,115- dichloro, 16a-methyl, 16fl-methyl, and l6a-acyloxy analogs of Formulae I, II and III. This modification depends solely on the choice of starting material employed, which in the present instance would involve the employment of a 3- and/or 'l7-keto-and-rostane possessing the desired substituent in the positions indicated, which substituents are introduced by methods (known in the art.

In addition, considered as equivalents to the novel 3 and/ or 17-lower alkanoylhydrazono-androstanes of this invention as exemplified by the compounds of Formulae I, II, and III, are those compounds of Formulae I, II, and III, wherein W is benzoyl or cyanoacetyl, e.g. androstan- 17,8-01-3-on 3-benzoylhydrazone, androstan-17,B-ol-3-one 3-cyanoacetylhydrazone.

It is, thus, apparent that this invention encompasses 3-l'ower alkanoylhydrazonesan drostanes of Formula I (i.e. when B is hydrogen); 3-dilower alkanoylhydrazonoandrostanes of Formula I (i.e. when B is lower alkanoyl); 17-lower alkanoylhydrazone-androstanes (when B is hydrogen or lower alkyl); and 3,17-bis-lower alkanoylhydrazono androstanes of Formula'II (i.e. when Z is monolower alkanoyl hydrazone); and the A A -analogs of the foregoing, as well as the 17-dilower alkanoylhydrazones of Formula III. Of the foregoing, the preferred class of compounds are the 3-mono-lower alkanoylandrostanes of Formula I since, as will be discussed furthenin this application, they possess a therapeutic activity superior to that possessed by other classes of compounds of this invention.

Illustrative of the 3-lower alkanoylhydrazono-androi stanes defined by Formula 1, including analogs thereof,- are compounds such as androstan-17fi-ol-3-one 3-acetylhydra zone and the l7-acetate and l7-cyclopentylpropionate esters thereof, 17u-methyl-androstan-17B-ol-3-one 3-acetylhydrazone, androstan17;8-ol-3-one B-formylhydrazone,

androstan-17B-ol-3-one 3-cyclopropylcanboxylic acid hy-- drazone; 17a-methyltestosteron 3-acetylhydrazone (ie 17a-methyl-4-androstan-17/3-ol-3-one 3-acetylhydrazone):;

17ot-methyl-l-dehydrotestosterone 3-acetylhydrazone, 19- nor-testosterone 3-acetylhydrazone, 17ot-ethinyl-19-nor-5 (10)-androsten-17fi-ol-3-one S-acetylhydrazone, l'la-ethinyltestosterone 3-acetylhydrazone, 1,4-androstadien-3,17- dione 3,l7-bis-monoacetylhydrazone, androstan-17fi-o1-3- one 3-acetylhydrazone; and the 3-dilower. alkanoylhydraa zono-A-ring-saturated androstanes such as androstan-IZB- ol-3-one 3-diacetylhydrazone and the 17-acetate ester thereof;

Typical 17-lower alkanoylhydrazono-androstanes of Formula [I are compounds such as androstan-3B-ol-17-one 3-acetate l7-N-methyl-N-acetylhydrazone, 1,4-androstadien-3,17-dione 17-acetylhydrazone, androstane-3,l7-dione 3,l7-bis-monoacetylhydrazone, androstane-3,l7-dione 17- acetylhydrazone.

Among the 17'dilower alkanoylhydrazono-androstanes of Formula III are derivatives such as androstane-3,l7- dione 17-diacetylhydrazone and androstane-3fl-ol-17-one 3-acetate 17-diacetylhydrazone.

Preferred compounds of this invention are the 3-monolower .alkanoylhydrazone derivatives of Formula I and, particularly the A-ring saturated analogs such as. androstan-l7 8-ol-3-one B-formylhydrazone, androstan-l7p-ol-3- one 3-acetylhydrazone and the l7-acetate esters, and the Hoe-methyl analogs thereof.

The 3- and/or 17-lower alkanoylhydrazones of A-ringsaturated androstanes are conveniently prepared by treating the corresponding 3- and/or 17-keto A-ring-saturated androstane with a lower alkanoylhydrazine in tetrahydrofuran or methanol/ acetic acid to obtain directly the corresponding 3 and/or l7-substituted hydrazone derivative. Thus, androstan-17B-ol-3-one upon treatment with monoacetylhydrazine in tetrahydrofuran, for example, or

in methanol to which a catalytic amount of glacial acetic acid has been added, will yield androstan-17B-ol-3-one 3-- acetylhydrazone. Similarly, androstan 3,8 ol 17 one,

when treated with acetylhydrazine is converted to andro-- 'stan-3t3-ol-l7-one 17-acetylhydrazone.

When preparing A-ring-unsaturated androstane. lolwer alkanoylhydrazone derivatives of Formulae I and II'by the aforedescribed process, i.e., by the action of an acylhydrazine, the choice of solvent medium is critical. If tetrahydrofuran alone is used as solvent, derivatives at C-17 only will form even when there are .3-keto groups present; whereas, if methanol/ acetic acid is used, substituted hydrazone derivatives will form at 0-3 as well as at C-17. Thus, when preparing 1,4-androstadiene-3,l7-dione 17- acetylhydrazone, for example, a method of choice is to heat at reflux temperature a mixture of molar equivalent weights 1,4-androstadiene-3,17-dione and acetylhydrazone in tetrahydrofuran. On the other hand ,When preparing the 3-acetylhydrazone derivative of 17a-ethinyl-19-nortestosterone, for example, a method of choice is to heat at reflux temperature a mixture of 17a-ethinyl-19-nor testosterone (i.e., 17u-etl1inyl-19-nor-4-androstene-1713-01- 3-one) and a molar equivalent of acetylhydrazone in' methanol/ aceti acid.

I The 17-lower alkanoylhydrazone derivatives of A-ring saturated androstanes and of ,A-ring unsaturated androstanes are also prepared=via a two-step synthesis whereby the unsubstituted hydrazone function is first introduced.

such as by reaction of a 17-keto-androstane, e.g., androstan-3/3-ol 17-one, with aqueous hydrazine :in ethanol and triethylaminet according to known procedures. The unsubstituted hydrazono-androstane thereby produced, e.g., androstan-3B-0l-l7-0ne 17-hydrazone, upon treatment with an acidanhydride (e.g., acetic or propionicacid anhydridei) in pyridine is;converted to=the corresponding acylhydrazone derivative with any free primary orsecondary hydroxyl groups being concomitantly esterified, e.g., an-

drostan-3fi-ol-l7-one 3-aceta-te .17-acetylhydrazone',

The;3,17-bis-monosubstituted hydrazono-androstanes of this invention, i.e., those compoundsSdefinedby Formula II wherein B is hydrogen and Z is a monosubstituted hydrazone, are preparedfrom the corresponding. -3,17-.

diketo-androstanes utilizing techniques similar to those for preparing the 3-monosubstituted.hydrazono-androstanes 1 except that longer reaction times=and a larger quantity of reagentare employed. Thus, 3,17-dilret-o-androstaues such as. androstane-3,17-dione and, 1,4-androstadiener3,17-dione upon treatment at room temperature for several. hours; (e.g. 10+18 hours) with at leasttwo molar equivalents of a monoacylhydrazine, e.g.,,acetylhydrazine, in meth- I anol/ acetic acid are each converted to the corresponding 3,17-bis-monoacetylhydrazone derivative.

action time, it is possible even when utilizing an acetic acid/methanol medium to prepare the 17-hydrazone de-- rivative without prior protection of the'reacting 3-keto,

group. This, then providesau alternative route for preparing 3-keto-17-lower alkanoylhydrazone-l,4-androstadienes in addition to the-aforedescribedprocedure utilizing tetrahydrofuran as solvent.

3,17-dione '17-acetylhydrazone; whereas, after eighteen hours, the 3,17-disubstituted derivative is isolated, i.e., 1,4- androstadiene-3, 17-dione 3,l7-bis-monoacetylhydrazone,

Similarly, by controllingreaction:time, temperature, and-quantity of reagent, the l7-mono-substituted=deriva! tive of a 'l7-keto-androstane havinga 3-keto-A -system may be prepared without-prior protectionof the reactive 3-keto group.

A .novel process of [this inventionwhereby 'a'loWer, alkanoylhydrazone function-is introducedzat C's-17 in 17- I keto-A-'ringrsaturated-androstanes not having a 3-keto group (e.g., androstan-BB-ol-17one) and .in 17-keto-A-" ring-unsaturated androstanes (e.g.,: 1,4-androstadiene-3,1'l-

dione) involves the introduction of a 17-hydrazine group via the action of potassium azodicarboxylate N-COOK ll N-COOK In :A-ring un-V saturated androstanes having keto groups both at C-3 and C-l7, the .keto group 'at C-l'iforms an acylhydrazone derivative at a much faster: rate than :does the keto group at 0-3. In those starting androstenediones having a 17- I keto group and a 3-keto-'1,4-diene system, the difference in the rate of hydrazone formation is such that, by proper control of reaction conditions such as restricting the re-- Thus, when 1,4-andro-= stadiene-3,l7-dione is subjectedto the action of about two moles of acetylhydrazine in methanol to whichacetic acid. has been added, for but an hour at room temperature,: there is isolated the :17-mono derivative, 1,4-androstadiene-t,

androstane product will become contaminated with a steroidal azine product.

To prepare a 17-mono-suflastituted hydrazone derivative of a 3,17-diketo-androstane having a saturated A-ring, there may be utilized the following novel multi-step process. By this process, a 3,17-bis-lower alkanoylhydrazonoandrostane is allowed to react with an acid anhydride preferably an anhydride of the same acid as the acyl substituent on the acylhydrazone function whereby there is formed the corresponding 3-keto-17-dilower alkanoylhydrazone derivative. Treatment of the 3-keto-l7-dilower alkanoylhydrazono-andr ostane with reagents such as zinc in ethanol, zinc in acetic acid or an alkali metal hydroxide in a lower alkanol results in the formation of the desired 3-keto-17-monoacylhydrazono-androstane. Thus, for example, androstane-3,17-dione upon reaction with about two molar equivalents of acetylhydrazine is converted to androstane 3,17 dione 3,17 bis monoacetylhydrazone, which, in turn, is treated with refluxing acetic anhydride to form androstane 3,17 dione 17 diacetylhydrazone, which, upon reaction with potassium hydroxide in ethanol yields the desired 3-keto-17-mono-substituted hydrazone, androstane-3,17-dione 17-acetylhydrazone. This procedure is the method of choice when preparing a 3-keto-l7- substituted hydrazono-A-ring-saturated-androstane, since each step of this procedure results in high yields.

Alternatively, a 3-keto-17-lower alkanolyhydrazone of Formula II may be prepared via a four-step procedure utilizing a 3-keto-17-hydroxyandrostane as starting compound. According to this alternate procedure, the keto group at C3 is first protected by known methods such as by formation of a ketal derivative, followed by oxidation of the 17-hydroxyl function, conversion of the thereby.

formed 17-keto group to an acylhydr-azone derivative and finally hydrolysis of the 3-keto protective group. For example, androstan-l7B-ol-3-one, upon treatment with ethylene glycol in the presence of an acid catalyst, yields 3- ethylenedioxy-androstan-l7f3-ol, which upon oxidation with chromic acid in pyridine yields the 17-keto compound, 3ethylenedioxy-androstan-l7-one, and treatment thereof with acetylhydrazine in methanol/ acetic acid yields 3 ethylenedioxy androstan-l7-one l7-acetylhydrazone. Regeneration of the 3-keto function via known procedures such as with dilute aqueous acetic acid yields androstane- 3,l7-dione 17-acetylhydrazone.

The aforedescribed alternate procedure is also useful when preparing a 17-acylhydrazone derivative of an androstane having a 3-keto-A -system. Thus, testosterone, after conversion to 3-ethylenedioxy-5-androsten-l7fi-ol, is oxidized at -17 by means of chromic acid in pyridine to produce 3-ethylenedioxy-5-androsten-17-one, which upon treatment with acetylhydrazine in tetrahydrofuran or acetic acid/methanol yields 3-ethylenedioxy-S-androsten-17- one 17-acetylhydrazone. Regeneration of the S-keto function such as with aqueous acetic acid yields 4-androstene3,l7-dione l7-acetylhydrazone.

The 3-dilower alkanoylhydrazone derivatives of this invention, i.e., those compounds defined by Formula I wherein B and W are both lower alkanoyl functions and wherein the androstane molecule has a saturated A-ring are preferentially prepared via a novel process of this invention whereby a S-keto-A-ring-saturated androstane, e.g., androstan-17 8-ol-3-one or the 17-acetate thereof is treated with ammonia and hydroxylamine-O sudfonic acid to yield a 3-diaziridine intermediate III, e.g., 3-diaziridineandrostan-l7B-ol which upon treatment with an acid anhydride in pyridine, e.g., acetic anhydride, will yield the desired 3-d ilower alkanoylhydrazone androstane of Formula I, e.g., the 3-diacetylhydrazone of androstane-17501 3-one 17-acetate, which under mild hydrolysis conditions such as with dilute methanolic potassium hydroxide at room temperature will yield the corresponding l7-'hydroxy derivative (1"). The above procedure is specific for the preparation of 3-diacylhydrazone of 3-keto-A-ring saturated androstanes only. This procedure may be depicted by a structural formulae flow diagram as follows wherein X and Y are defined as for formulae I-III.

The yields for each step in the above procedure are excellent, making this the procedure of choice over an alternative process analogous to known procedures whereby there is first prepared a semicar-bazone derivative at C3 followed by treatment with an acid anhydride in pyridine to yield the 3-diacylhydrazone (such as 1' above).

The 17 N-alkyl-N-lower alkanoylhydrazone androstanes of Formula II, i.e., those compounds wherein B is lower alkyl, are conveniently prepared from the corresponding 17-keto-androstane by first introducing a monoalkylhydrazone function by reaction with a monoalkylhydrazine according to known methods, followed by treatment of the thereby formed 17-N-alkylhydrazonoandrostane with an acid anhydride in pyridine to obtain the corresponding N-alkyl-N-acylhydrazone. Thus, for example, androstan-3j3-ol-l7-one upon treatment with methylhydrazine according to known procedures is converted to androstan-3B-ol-l7-one 17-N-methylhydrazone, which upon treatment with acetic anhydride in pyridine yields the l7-di-substituted hydrazone, i.e., androstan-3fiol-l7-one l7-N-methyl -N acety'lhydrazone. Treatment with other lower alkanoic acid anhydrides, such as caproic acid anhydride, will yield the corresponding N-methyl- N-acyl derivative, i.e., androstan-3B-ol-l7-one 17-N- methyl-17-N-caproylhydrazone.

In preparing the novel 3- or l7-substituted hydrazonoiandrostanes of this invention, it is usually preferable to have all the desired substituents at C9 and 11, for example, present in the starting 3- and/or 17-keto-androstane. Thus, when preparing androstane-115,17B-diol- 3-one 3-acetylhydrazone and the L-flUOI'O analog thereof, one preferably utilizes as starting derivative androstane- 1lB,l7,8-diol-3-one and 9u-fluoro-androstane-1113,17/3-dio1- 3-one, respectively.

When preparing the 17-N-alkyl-N-lower alkanoylhy drazones of this invention or when employing the aforedescribed two-step general synthesis for the preparation of 17-monoacylhydrazones (i.e., by first introducing the hydrazone function followed by acetic anhydride treatment) any free secondary or primary hydroxyl group present will be esterified during the step involving treatment with a lower alkanoic acid anhydride in pyridine. If desired, such ester function may be hydrolyzed to the corresponding free hydroxy compound by mild methanolic potassium hydroxide treatment.

In general, 3- and/or l7-keto-androstanes, necessary Of the. monoacylhydrazine reagents utilized in;pre-;.- paring our novel compounds, many are known,-such as acetylhydrazine, benzoylhydrazine, formylhydrazine, cy-.

anoacetylhydrazine, and the like. If a desired monoacylhydrazone is not available, it can be conveniently prepared utilizing known procedures, i.e., by treating anhydrous hydrazine (i.e., 95%) with a lower carboxylic acid ester, e.g., ethyl acetate, at about 100C. to obtain the corresponding lower carboxoyl hydrazine (i-.e., acetylhydrazine) Similarly, many of the monoalkylhydrazine' intermedi-; ates are known, such as monomethylhydrazine and mono-- ethylhydrazine. If not available, a monoalkylhydrazine is conveniently prepared in known manner by treating a substituted urea with a hypohalite, e.g., hypochlorite,or@

by treating an appropriate alkylamine with chloramine prepared in situ from sodium hypochlorite and am-.

monium hydroxide.

The substituted hydrazone derivatives of saturated androstanes such as defined by Formulae I and ILas well as the 4-dehydro-, l,4-bis-dehydro-, and l9-nor-4-dehydro:

analogs thereof, possess androgenic/anabolic activity and maybe administered in an analogous manner andv for thesame indications as known androgenic/anabolic agents. Of the foregoing, the 3-lower alkanoylhydrazone A-ring saturatedderivatives of Formula I are preferred sincethey possess the most favorable ration of anabolic/ androgenic. activity.

The 3 -lower alkanoylhydrazono-l9-nor-5 10) -dehydroandrostanes of Formula I have been found to possess anti-fertility activity in rats. Additionally, -tl1ese.compounds are active as intermediates in the preparation of 3 alkanoylhydrazono-IO-hydroperoxy-19-no r-A -steroids.

For example, upon introduction of oxygen into a methylene chloride/hexane solution of 17a-ethinyl-19-nor-5 (l0)-androsten-l7,8-ol-3-one 3-acetylhydrazone, there is obtained lO-hydroperoxy-l7a-ethinyl-19-nor-4-androsten- 17B-o1-3-one 3-acetylhydrazone which possesses anti-i fertility activity.

The following examples are for illustrative purposes only and not to be construed as limiting, the limit of our invention being defined by the appended claims:

EXAMPLE 1 5 a-androstan-l 7,8-01-3-0112 3-acetyl/zydraz0ne 1 7-acetate I Reflux for one hour a mixture of 1 g. of 5a-androstan-.

l7fl-ol-3-0ne l7-acetate and l g. of monoacetylhydrazine in 10 ml. of tetrahydrofuran. Cool the reaction mixtureand filter the resultant precipitate comprising 50candrostan-l7fi-ol-3-one 3-acetylhydrazone l7 acetate. Purify .by crystallization from acetone-hexane. M.P. 245-248 C., [OC]D +15.8.

EXAMPLE 2 Sa-andrOstan-I7B-0l-3-0ne 3-acetylhydrazbne To a solution of 1 g. of 5u-androstan-l7B-ol-3-one in 20 ml. of tetrahydrofuran, add' 1 g. of monoacetylhydral zine. Refluxthe reaction mixture for one-half hour; then cool to room temperatureand filter the resultant precipitate comprising 5a-androstan l7fl-ol-3-one S-acetyl- 8f hydrazone; Purify by crystallization from aqueous methe a-nol. 232-2'35-C., [ot] |'15.2.,.

EXAMPLES 5a-andr0stan-17B-0l-3-one 3-acetylhydrazone 17-cyclopentylpr0pi0nate I A. 5a-ANDROSTAN-l7B-OL-3-ONE17-CYCLOPENTYL- PROPIONATE To' 3.04 g. of Su-androstan-17/3-ol-3 one in 50 m1. of dry distilled pyridine chilled'to 0-10.? CE, add dropwise with stirring 5 g.;of; cyclopentylpropipnyl chloride; .Stir the reaction mixture forabout 12 hours at room temperatureythen pour with stirringrinto a mixture of 400 g. of ice and *ml. of concentrated sulfuric acid.; Ex-v tract the: acidic: mixture with benzene; then wash .the. combined benzene extracts first with 10% sodium car bonate,- then with water. Dry the .rwashed benzene solution over. magnesium sulfate; thenaevaporateto anioilyv residue comprising v5oa-androstan 17 3-ol-3-one; :17-cycl0- pentylpropionate. Iurify'by chromatography on alumina eluting first with hexane,.then with 1:1 hexane ben zene,

andfiually with benzene. Combineytheq benzene .eluates andevaporate to a residue of 5a-androstan-l7fl-ol-3-one 17-cyclopentylpropionate..

B. fia-ANDROSTAN-l'IB-OL-3-ONE 3AGETYLHYDRA ZONE 17 -CYCLOPENTYLPROPIONATE To a solution of 1 g. of 5u-androstan l7 8-ol-3-one .17- cyclopentylpropionate in 20ml. of tetrahydrofuran, add

200 mg. of monoacetylhydrazine. Reflux the mixture for one-half'hour; then pour into 200 rnlrof 'water and filter the resultant precipitate comprising.5a-androstan117fi-ol-' 3-one 3-acetylhydrazone 17 -cyclopentylpropionate. .Pur-

ify' by' crystallization twice fromzmethanol. f M.P. '207- Y 21.1 C., [aJ +221.

I EXAMPLE 4 5oc-llfldl'0SlLZfl-3B-Ol-I7-0118 S-acetate 17-acetylhydraz0ne A. fia-ANDROSTAN-3B-OL-17-ONE '17-VHYDR'AZVONE To a solutionof=1 g. of 5a-androstan-3fl-ol-17-one .in 10 ml. of dry ethanol, add *Z'ml. .oftriethylamine and 6 m1. of 65% aqueoushydrazine- Reflux the reaction mix ture for 2 hours; cool; pour into 200 ml. of water; then filter and dry the; resultantv precipitate. substantially of 5a-androstan-3p-ol-l7-one" 17-hydrazone. crystal'lation from rmethylene chloride/isopropyl ether. M.P. 260-268. C., [0:] +485.

Alternatively, the-compound of this example ;is pre-. pared as follows: a

To a solutionofl g. of 5aaandrostan-3fi-ol-17-one in 20 ml. of methanol and 3.5 ml. of acetic. acid, add with stirring over. a fifteen minute .period, 3 g.- of potassium 1 azadicarboxylatea Stir the reaction. mixture at room 1 temperature for two hours; then pour.into120.0 ml. of water and filter and dry the resultantprecipitate com-' prising 5a-androstan-3 8-o1-17-one 17-hydrazone. Purify in the .manner described .in Example 4A.

B. 5a-ANDROSTAN-3BOL-17ONE 3-ACETATE 17- ACETYLHYDRAZONE Dissolve -1 ,g. of 5a-androstan-3fi-ol-17-one .17#hydra-- zonezin 10 ml. ofpyridineand 1 ml. of. acetic anhydride and allow the solution to stand at room temperature for .18 hours. Water andfilter and .dry the resultant precipitate com- Pour the reaction mixture into 100 ml. of

prising 5a-androstan-3fl-ol-17-one 3-acetate17-acetylhydrazone. Purify by crystallization :from methylenechloride-hexane. M.P. 203-206 Cr, [a] +57..4.:

Alternatively, treatment of '5ir-androstan-3t8-ol-l7-onev 3-acetate with :monoaoetyl hydrazine 'in tetrahydrofuran according to the procedureof Example '1 followed by isolation of the resultantproduct inthe described manner will yield 5a.-androstau-3fi-ol-17rone 3-acetate .17-aeetylhydrazone.

Purify by a 9 EXAMPLE 5 5 a-andrstan-3B-0l-1 7-0ne 3-acetate 1 7-N-methylacetylhydrazone A. a-ANDROSTAN-3B-OL17-ONE 17 METHYL- HYDRAZONE Add 1 g. of .5u-androstaufl-ol-fl-one to ml. of methylhydrazine and reflux the mixture for 17 hours. Cool the reaction mixture; then pour into water and filter and air dry the resultant precipitate comprising Six-androstan-3i3-ol-17-one 17-methylhydrazone. Purify by crystallization twice from acetone-hexane. M.P. 130155 C. (dec.), [0:1 +729.

B. 5a-ANDROSTAN-3B-OL-17-ONE 3-ACE'1ATE 17+N- METHYL-ACETYLHYDRAZONE Dissolve 1 g. of 5ot-androstan-3B-ol-17-one 17-methylhydrazone in 10 ml. of pyridine and 1 m1. of acetic anhydride. Allow the solution to stand at room temperature for 18 hours; then add 1 ml. of water and pour the reaction mixture into 100 ml. of water. Filter the resultant precipitate comprising 5a-androstan-3f3-ol-17- one B-acetate 17-N-methyl-aoetylhydrazone. Purify by crystallization from acetone-hexane. M.P. 193-195" C., [(111) +l163-7- EXAMPLE 6 1 7a-metlzyl-5 a-androstan-I 75-01-3 -one 3 -acety lhydrazone Allow a mixture of 1 g. of l7u methyl-5a-androstan- 17B-ol-3-one and 1.2 g. of acetylhydrazine in 40 ml. of methanol and 0.8 ml. of acetic acid to reflux for one hour. Pour the reaction mixture into 400 ml. of water and filter and dry the resultant precipitate comprising 17a methyl-5aaandrostan-l7;8-ol-3-one 3-acetylhydrazone. Purify by crystallization from methylene chloride-hexane. M.P. 2 60-264 0., [L11 40.

Alternatively, the compound of this example is prepared as follows:

To a solution of 1g. of l7a-methyl-5a-androstan-17,8- ol-3-one in 20 ml. of tetrahydrofuran, add 1 g. of monoacetyl-hydrazine. Reflux the reaction mixture for one hour; than cool and pour into 200 ml. of water. Filter the resultant precipitate comprising 17ot-methyl-5a-androstan-17/3-ol-3-one 3-acetylhydrazone and purify in the manner described above.

EXAMPLE 7 5 u-androstan-J 7 B-0l-3-0ne 3-formylhydrazone To a solution of 1 g. of SOL-HDdI'OStaH-17,3-01-3-0116 in 40 ml. of methanol and 0.8 ml. of glacial acetic acid, add 2.0 g. of formylhydrazine. Reflux the reaction mixture for 2 hours; then pour into 400 ml. of water and filter and dry the resultant precipitate substantially of 5a-androstan-17/3-ol-3-one 3-formylhydrazone. Purify by crystallization from methylene chloride-methanol-hexane. M.P. 255-260/C., [ab +193.

EXAMPLE 8 5a-andr0stan-17f3-ol-3-one 3-cycl0propylcarboxylic acid hydrazone Reflux for 2 hours a mixture of 1 g. of 5a-androstan- 17B-ol-3-one and 2 g. of cyclopropylcarboxylic acid hydrazide in 40 ml. of methanol and 0.8 ml. of glacial acetic acid. Pour the cooled, reaction mixture into 400 m1. of water and filter and dry resultant precipitate comprising fia-androstan-17,6-o1-3-one 3-cyclopropylcarboxylic acid hydrazone. Purify by crystallization from methylene chloride-hexane. M.P. 244248 C., [@1

EXAMPLE 9 1,4-androstadiene-3,11,17-tri0ne 17-acetylhydraz0ne A. 1,4-ANDROSTADIENE3,11,17-TRIONE l7-HYDRAZONE To a stirred solution of 5 g. of 1,4-androstadiene- 3,11,17-trione in 200 ml. of methanol and 35 ml. of glacial acetic acid under an atmosphere of nitrogen, add

portionwise over a one-half hour period 30 g. of solid potassium azodicarboxyl-ate and stir the reaction mixture an additional hour. Pour the reaction mixture into water; extract with methylene chloride; wash the combined extracts with water; then dry over magnesium sulfate and concentrate in vacuo to a residue substantially of l,4-androstadiene-3,'11,17-trione 17-hydrazone, which is used without further purification in Example 9B.

Purification can be effected by crystallization from acetone-hexane. M.P. 172l79 C. (dec.), [u] +123.1. +123.1.

B. lA-ANDROSTADIENE-3,11,17-TRIO1NE 17-ACETYLHYDRAZONE To the 1,4-androstadiene-3,11,17-trione l7-hydrazo-ne prepared in Example 9A, add 40 ml. of pyridine and 8 ml. of acetic anhydride and allow the mixture to stand overnight. Extract the reaction mixture with methylene chloride; wash the combined extracts with water, dry over magnesium sulfate, and concentrate in vacuo to a residue substantially of 1,4-andr0stradiene-3,11,17-trione 17- acetylhydrazone. Purify by sublimation at 200-220 C. (5.8 then crystallize the sublimed solid from acetonehexane. M.P. 263-266 C., [u] +1821.

EXAMPLE 1O 1,4-andr0stradiene-3,17-di0ne 17-acetylhydraz0ne In a manner similar to that described in Example 1, allow 1,4-androstadiene-3, 17-dione to react with monoacetyl-hydrazine in tetrahydrofuran. Isolate and purify the resultant product in the described manner to give l,4-androstadiene-3,17-d-ione 17-acetylhydrazone.

Alternatively, the compound of this example is prepared as follows:

To a solution of 1 g. of 1,4-androstadiene-3,l7-dione in 20 ml. of methanol and 0.8 m1. of glacial acetic acid, add 1.2 g. of acetylhydrazine. Allow the reaction mixture to stand at rom temperature for one hour; then pour into water and extract with methylene chloride. Wash the combined extracts with water, dry over magnesium sulfate, and concentrate in vacuo to a residue substantially of 1,4-androstadiene-3,17-dione 17-acetylhydrazone. Purify by crystallization from acetone-hexane. M.P. 238241 C., [oc] +130.

Purification can also be effected by sublimation at 220 C. (20;!) followed by crystallization from aqueous acetone.

EXAMPLE 1 1 1 7 u-melhyl-4 -umdrosten-1 7fi-0l-3-0ne 3 -acetylhydraz0ne To a solution of 1 g. of 17a-methyl-4-androsten-17f?- ol-3-one in 20 ml. of methanol and 0.8 ml. of glacial acetic acid, add 1.2 g. of acetylhydrazine. Allow the reaction mixture to stand at room temperature for 18 hours; then pour into 200 m1. of water and filter and dry the resultant precipitate comprising l7a-methyl-4-androsten- 17Bol-3-one S-acetylhydrazone. Purify by crystallization from acetone-hexane. M.P. 142148 C., (bubbling dec.), [oc] +1872.

EXAMPLE 12 1 7a-methyl-1,4-androstadien-1 7 fl-0l-3 'One 3 -acety lhydrazone .1 EXAMPLE 13 a-androstan-l 7 fi-ol-S-one 3-cyan0acetylhydraz0ne Dissolve 1 g. of 5a-andr0stan-17/i-ol-3-one in 20 ml. of warm methanol and 0.8 ml. of acetic'acid. Add 2 g. of

cyanoacetylhydrazine, then 20 ml. of methanol and reflux the resultant heavy suspension for one-half hour.

resultant precipitate comprising 5a-androstan-l7,Bol-3- one 3-cyanoacetylhydrazone. Purify by crystallization from methylene chloride/methanol. M.P. 230-233 C. (bubbling dec.), [ad +206.

EXAMPLE 14 19-nor-4-androsten-1 7f3-0l-3-0ne 3-acetylhydraz0ne Cool; the reaction mixture, add 80' ml. of water, and filter; the

Stir at room temperature until a clear solution is ob-.;

7 tained a mixture of 1 g. of 19-nor-4-androsten-175-01-3- one and 1 g. of monoacetylhydrazine in 20 ml. of methanol and 0.8 ml. of glacial acetic acid. After. solution is eflected, continue stirring for 18 hours; then pour into water. Extract the reaction mixture with methylene chloride; then wash the combined extracts with water, dry

over magnesium sulfate and concentrate in vacuo to a residue comprising 19-nor-4androsten-17,8-01-3-one 3-' acetylhydrazone. Purify, by crystallization from acetonehexane. M.P. 226-232 0., [1x1 +173.1.

EXAMPLE 15 1 7a-ethinyl-1 9-nor-4-androsten-1 7 ,B-0l-3-0ne 3-acetylhydraz0ne To 1.75 g. of 17a-ethinyl-19-nor-4-androsten-171%01-3- one, add a solution of 1.75g. of acetylhydrazine in ml..

of methanol and 1.2 ml. of glacial acetic acid. Heat-the solution at reflux temperature for one hour; then pour into 400 ml. of water and filter the resultant precipitate comprising 17u-ethinyl-l9-nor-4-androsten-17,8-01-3 one 3-acetylhydrazone. Purify by crystallization from acetone-hexane. M.P. 157-162. C.

EXAMPLE l6 5ot-andr0sran-17/3-0l-3-0ne 3-benz0ylhydraz0ne.

Dissolve 1 g. of Sa-andmstan-l7fi-ol-3-one in 40 ml. of methanol and 0.8 ml. of acetic acid; then add 2 g. of benzoylhydrazine. Reflux the reaction mixture for onehalf hour; then dilute with '80 ml. of Water and cool. Filter .and-air-dry the resultant precipitate comprising 5ozandrostan-17B-ol-3-one 3-benzoylhydrazone. Purify by crystallization from methanol. M.P. 196-199" (3., [adj +7.9.

' EXAMPLE 17 1,4-andr0szadiene-3J7-di0ne 3,1 7-bismonoacetylhydrazone 5 a-androstane-3J 7 -di0ne 1 7 -acety lhydrazone A. oa-ANDROSTANE-3,17 DIONE' lT-DI ACETYLHYDRAZONE Add 1 g. of 5a-androstane-3,17-dione 3,17-bis-monoacetylhydrazone to 10 m1. of acetic anhydride. Stirat room temperature for 15 minutes; then'heat at reflux 12. temperature for one .hour. .Cooland pour the" reaction mixture into 100 ml. of water and stir the mixtureat room temperature for one hour.: Filter and air-dry the resultant preciptate :comprising. '5a-androstane-3,17-dione 17-diace-tylhydrazone.- Purify by chromatography on silica gel eluting with 50% ethyl acetate/ chloroform. Combine those fractions containing. 5ct-,androstane-3,17-dione 17-diacetylhydrazone asdetermined byginfrared spectra and thin layer chromatography, Evaporate and crystallize the resultant residue from acetone-hexane.

B. 5a-ANDROS1ANE-3,17..-DIONE:17-ACETYLHYDRAZONE To a solution of 1 g. of 5 t-androstane-3,17;-dione:17- diacetylhydrazone in ml. of ethanol, add a solution of 1 g. of potassium hydroxide in 10 ml. of water. Heat the reaction mixture at reflux temperature 'for one hour; then cool and dilute with 400 .ml. of methylene chloride. Wash the organic solution with water to neutrality; then dry over magnesium sulfate and concentrate toa residue comprising 5a-androstane-3,17-dione :17-acety-lhydrazone, 1

Purify by crystallizationfrom acetone-hexane.

. EXAMPLE '19 5 a-androstan-I 75-0l-30ne 1 7 acetate 3 -diacetylhydmzone' The requisite starting material, i.e., 5ot-androstan17[3- o1-3-one B-semicarbizone. is preparedby treating. Soc-am r drostan-17B-ol-3-one with semicarbazide hydrochloride and sodium acetate .intmethanol according. to known procedures.

To a solution of 4.8. g. of Su-andrOstan-I7,6-ol-3-one 3- semicarbazone in 96 ml. of pyridine, add 48 ml. of acetic anhydride and heat at reflux temperature for 5 hours. Concentrate-the reaction mixture irr vacuo to a residue comprising 5u-androstan-l7.8-ol 3-one :17-acetate 3-diace-. tylhydrazone.- Purify bychromatography on silica :gel eluting with chloroform/ethyl. acetate (9:1'). Combine those fractions containing -5u-androstan-17fl-ol 3-one 1 7-" acetate-3-diacetylhy-drazone.as determined by thin layer chromatography and infrared spectra. Evaporatethe combined fractions to a residue and crystallize the residue from methanol/ water and recrystallize from aqueous ace- I tone.- M.P. 224228 (3., [@1 +129.

EXAMPLE 20 5 wandroslan-l 7/3-0l-3-ane 3-.diacetylhydraz0ne Add 1 g. of i5u-andros-tan-l7fi-ol-3-one 17-acetate. 3- diacetylhydrazone to 100 ml; of 10% ethanolic potassium hydroxide.- Heat the reaction mixturexat reflux temperature for one hour; then cool and dilute with '100 ml. of methylene chloride. Wash the organic solution with water; then dry over magnesium sulfate and evaporate in vacuo to a .residue comprising Sa-androstan-Ufiol-3-one 3-diacetylhydrazone. Purify by crystallization from isopropanol/water. M.P. .206+208 0., [0th, +15.6.

EXAMPLE 21 jot-[Zildl'OSHZI'l-3fi-Ol-17-0113 3-acezate'l 7-diacetylhydrazone 7 Add 1 got '5oz-andr0stan-3fi-0l-l7-0ne-3-acetate 17- acetylhydrazone .(the compoundof Example 4B) to 10 ml.:of acetic anhydride and heat at reflux temperature for one hour. Concentrate the reaction mixture to a volume of 5 ml; then cool. cipiate comprising Soc-3.11Cl10St21Il-3fi-Ol-17-OI1G 3-acetate l7-diacetylhydrazone. Purify by crystallization from acetone-hexane. M.P. ZOO-204 C., [ab +26.

EXAMPLE 22 17ot-ethlinyl-19-1n0r-5 (10)-tmdr0sten-1 7 fl-0l-3 -0ne 3-acetylhydrazone.

To a solution of 1 g. of 17a-ethinyl-19-nor-5(10)-androsten-17fi-ol-3-one in 15 ml of methanol, add 1 g. of monoacetylhydrazine and immediately add .0.8 ml. of glacial acetic acid. To the precipitate which'forms, add

Filter the resultant pre- EXAMPLE 25 ot-andr0stan-17fi-0l-3-0ne 3-diacetylhydrazone A. 3-DIAZIRIDINE-5-ANDROSTAN-17B-OL To 266 ml. of liquid ammonia cooled ina Dry'Iceacetone bath, add a solution of g. of 5a-androstan-l7fiol-3-one in 266 ml. of absolute ethanol. Stir this mixture for 10 minutes in the Dry Ice-acetone bath; then add 4-86 g. of hydroxylamine-O-sulfonic acid and continue stirring at 40 C. for two hours. Allow the reaction mixture to slowly rise to room temperature and the am-;

monia to evaporate; then air evaporate the solution to a residue. Extract the residue with refluxing ether at least four times. Dry combined ether extracts oversodium sulfate; then concentrate to a residue comprising 3-diaziridine-Sa-androstan-l713-01. This compound is used with out purification in procedure B immediately following.

In a similar manner, allow each of the following 50ctestosterone. derivatives to react with hydroxylamine-O-.

sulfonic acid:

17a-methyl-5a-androstan-17B-o1-3-one;

9u-flu0ro-17a-methyl-5u-androstane-11,8,l7B-diol-3-one,

and l 17u-methyl-5a-androstane-1 1,8,175-diol-3-one.

Isolate and purify each'of the resultant products in a manner similar to that described above to obtain, respectively:

3-diaziridine-l7a-methyl-5u-androstan-175-01,

3-diaziridine-9u-fluoro-17a-methyl-5a-androstane- 11B,17,B-diol, and

3-diaziridinel7a-methyl-5a-androstane-1 15,17 8-dio1.

B. 5a-ANDROSTAN-17B-OL-3-ONE 3-DIACETYL- HYDRAZONE 177ACECLATE Dissolve 1 g. of 3-diaziridine-Sa-androstan-176-01 (prepared in preceding Example'ZSA) in 10 ml. of pyridine and 1 ml. of acetic anhydride. Allow the solution to stand at room temperature for 18 hours; then add 1 ml. of

water and pour the reaction mixture into 100 ml. of water. Filter the resultant precipitate comprising Sa-androstan- 17fl-ol-3-one 3-diacetylhydrazone l7-acetate. Purify by crystallization from acetone-hexane.

In a similar manner, allow each of the 3-diaziridine derivatives prepared as described in the second paragraph of Example A to react with acetic anhydride and pyridine to obtain, respectively;

17a-methyl-5u-androstan-17B-ol-3-one,

3-diacetylhydrazone,

9u-fluoro-17a-rnethyl-5oc-androstane-1 1,8, l7B-diol-3-one,

3-diacetylhydrazone, and

17a-methyl5-androstane'115,175-dio1-3-one 3-diacetyli hydrazone.

C. 5a-ANDROSTAN-17fl-OL-3-ONE-3-DIACETYL- HYDRAZONE In a manner similar to that described in Example 20, allow 5a-androstan-17,3-01-3-one S-diacetylhydrazone 17- acetate to react with 10% ethanolic potassium hydroxide.

Isolateand purify the resultant product in a manner simi-. lar to that described to give 5tx-androstan-17fi-ol-3-one, Purify bycrystallization from iso- I 3-diacetylhydrazone. propanol/ water.

We claim:

1..A member selected from the group consisting of" androstanes of Formulae I and II, the 4-dehydro-, 1,4- bis-dehydro-, and 19-n0r-4-dehydro analogs thereof; and

the 19-nor-5 (l0)-dehydro analogs of Formula I:

wherein W. is lower alkanoyl; B isilowerfallranoylgB iista member selected fromthe group consisting of hydrogen' and lower alkyl;lX is amember selected from the group: consisting of hydrogen and=fiuT0rine;LY-.is a member se-- lected from thegroup consisting of hydrogen and (H5 ,BOH), andwhen Y.is hydrogemXis hydrogemZis member selected from-the group consisting of 5 R being a member. selected from the group ;consisting of, hydrogen and an acyl radical of a hydrocarbon 'carbox-:

ylic acidhaving up. to 8 :carbon atoms,,and A being a member selected from-the groupconsisting of hydrogen,=

ethinyl, and lower alkyl; and Z' being amemberselected from the group consisting of keto :and :lower alkanoyls, hydrazone, andwhen Z'= is lower; alkanoylhydrazone .B.

ishydro gen.

2. A'compound of claim 1 wherein B and .W are acetyl;

X and Y are'hydrogen, and Z is (H; BOB), said com pound having the name; androstan-17B-ol-3-one- 3-diacetylhydrazone.

3. A compound having the following structural formu-;

lower alkanoyl fi i lower alkanoyl wherein T 'is a member. selected :from the. group ;consist ing of keto and (H, R), Ribeing a member selected. from the group consisting of H and an, acyl radicalof a. hydrocarbon carboxylic acid having up. to 8 carbon atoms,

X is a member selected-from the group .consisting of hydrogen and fluorine; Y' is a member selected .from the.

ing up to 8 carbon atoms, Xis a membertselected from.

the group consisting of hydrogen and fluorine; and Y is a member selected from the group consisting of hydrogen and hydroxyl and when Y is hydrogen, X is hydrogen; and treating the thereby formed corresponding 17-hydrazone derivative in pyridine with an anhydride of a lower alkanoic acid to obtain the corresponding 17 -lower alkanolyhydrazone derivative.

5. The process for preparing Qa-X-l lB-Y-17-Z-5aandrostane-3-one 3-dilower alkanoylhydrazone wherein X is a member selected from the group consisting of hydrogen and fluorine; Y is a member selected from the group consisting of hydrogen and hydroxyl, and when Y is hydr-ogen,'X is hydrogen; and Z is a member selected from the group consisting of R being a member selected from the group consisting of hydrogen and an acyl radical of a hydrocarbon carboxylic acid having up to 8 carbon atoms, and A being a member selected from the group consisting of hydrogen and lower alkyl; which comprises reacting with ammonia and hydroXylamine-O-sulfonic acid, 9a-X-11B-Y-17-Z-5a-androstan-3-one wherein X, Y and Z are as defined hereinabove;

and reacting the thereby formed corresponding 3-diaziridine derivative with an anhydride of a lower alkanoic acid.

6. The process of preparing 9a-X-11fi-Y-5a-androstane-3,17-dione 17-l0wer alkanoylhydrazone wherein X is a member selected from the group consisting of hydrogen and fluorine; Y is a member selected from the group consisting of hydrogen and hydroxyl, and when Y is hydrogen, X is hydrogen; which comprises reacting 9a-X- 1l;8-Y-5a-androstane-3,17 dione 3,17 bis monoloweralkanoylhydrazone wherein X and Y are as hereinabove defined; with an anhydride of a lower alkanoic acid; and treating the thereby formed 9a-X-l1fi-Y-5a-androstane- 3,17-dione l7-dilower alkanoylhydrazone with a reagent selected from the group consisting of zinc in a lower alkyl alcohol, zinc in a lower alkanoic acid, and an alkali metal hydroxide in a lower alkanol.

7. The process of preparing a compound selected from the group consisting of 9a-X-l1-Y-5a-androstane-3,17- dione 17-monolower alkanoylhydrazone, and the 4-dehydroand 1,4-bis-dehydro analogs of the foregoing, wherein X is a member selected from the group consisting of hydrogen and fluorine, Y is a member selected from the group consisting of hydrogen and (H, BOH), and when Y is hydrogen, X is hydrogen; which comprises reacting a member selected from the group consisting of 9a-X-11- Y-5u-androstane-3,17-dione, the 4-dehydroand 1,4-bisdehydro-analogs of the foregoing, wherein X and Y are as hereinabove defined, with a lower alkanoylhydrazine in a solvent selected from the group consisting of :tetrahydrofuran and methanol/ acetic acid.

References Cited by the Examiner UNITED STATES PATENTS 2,200,307 5/1940 Schoeller et a1 260-397 2,306,635 12/1942 Marker 260397.1 3,032,469 5/1962 Gleason 167-65 OTHER REFERENCES Sidgwick: Organic Chemistry of Nitrogen, Oxford University Press London, pages 398-399 (1937).

LEWIS GOTTS, Primary Examiner.

HENRY FRENCH, Assistant Examiner. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF ANDROSTANES OF FORMULAE I AND II, THE 4-DEHYDRO-, 1,4BIS-DEHYDRO-, AND 19-NOR-4-DEHYDRO ANALOGS THEREOF; AND THE 19-NOR-5(10)-DEHYDRO ANALOGS OF FORMULA I:
 2. A COMPOUND OF CLAIM 1 WHEREIN B AND W ARE ACETYL, X AND Y ARE HYDROGEN, AND Z IS (H,BOH), SAID COMPOUND HAVING THE NAME ANDROSTAN-17B-OL-3-ONE 3-DIACETYLHYDRAZONE. 